Penumbra, ischemic

Qualitative analysis of perfusion images is usually based on two assumptions that are derived from the pathophysiologic principles discussed above. First, tissue with visibly decreased CBV is so severely ischemic that it is unlikely to survive and lies within the core of the infarct. Second, tissue with decreased CBF or prolonged MTT may be mildly or severely ischemic and may or may not be salvageable. If this tissue does not appear abnormal in another, more specific type of image (such as CBV or DWI), it represents the ischemic penumbra and may potentially be rescued by immediate therapy. 

However, the real promise of CTP lies not in its ability to detect acute stroke, but in its ability, like that of MRP, to distinguish between infarct core and the ischemic penumbra. CTP produces maps of the same perfusion parameters that are generated by MRP, and CTP maps are interpreted in a similar manner, with one important exception with CTP, DWI images are usually not available to identify the infarct core. Therefore, CBV maps are usually used to define the infarct core. Tissue that appears normal in CBV maps, but abnormal in CBF or MTT maps, is taken to represent the ischemic penumbra. 

Several studies have validated the ability of CTP to distinguish between core and penumbra. In one study, Wintermark et al. found that the volumes of early infarcts in CTP CBV maps were highly correlated with volumes of early DWI lesions, whereas volumes of lesions seen in CTP CBF maps were close to those seen in the corresponding MRP MTT maps. In another study, the volume of the CBF abnormahty in an acute-stage infarct was highly correlated with final infarct volume in patients who did not exhibit recanalization after thrombolysis, consistent with extension of infarction into the penumbra. However, in patients who did exhibit recanalization after thrombolysis, final infarct volume was highly correlated with the initial CBV abnormality, consistent with failure of infarcts to extend into the ischemic penumbra. ... 

Karonen JO, Vanninen RL, Liu Y, 0stergaard L, Kuikka JT, Nuutinen J, Vanninen EJ, Partanen PL, Vainio PA, Korbonen K, Perkio J, Roivainen R, Sivenius J, Aronen HJ. Combined diffusion and perfusion MRI with correlation to single-photon emission CT in acute ischemic stroke. Ischemic penumbra predicts infarct growth. Stroke 1999 30 1583-1590. 

Schlaug G, Benfield A, Baird AE, Siewert B, Lovblad KO, Parker RA, Edelman RR, Warach S. The ischemic penumbra operationally defined by diffusion and perfusion MRI. Neurology 1999 53 1528-1537. 

Astmp J, Siesjo BK, Symon L. Thresholds in cerebral ischemia - the ischemic penumbra. 

Furlan M, Marchal G, Viader F, Derlon JM, Baron JC. Spontaneous neurological recovery after stroke and the fate of the ischemic penumbra. Ann Neurol. 1996 40 216-226. 

Review of postcontrast CTA source images might provide a good estimate of whole-brain perfusion." If time allows, MR or CT perfusion maps are obtained to characterize more accurately the ischemic penumbra." Careful but expedited preprocedural analysis of the CTA, done in parallel with transport of the patient to the treatment area, may be extremely helpful in establishing the presence of anatomic variants (e.g., bovine aortic arch) or pathological states (e.g., vessel origin or carotid bifurcation disease) prior to the catheterization procedure. 

The GP Ilb-IIIa complex inhibitor Tirofiban has been used as an adjunct to thrombolysis in a number of small case series reports." A small transcranial Doppler (TCD) study suggests that it reduces microembolization from unstable carotid plaque." In an open pilot smdy, Tirohban administered within 9 hours after stroke onset blocked the conversion of ischemic penumbra to mature infarction." A phase III study (SETIS) has started recruiting patients to investigate its efficacy versus aspirin within the 6-hour window. 

Liu S, Shi H, Liu W, Eumichi T, Timmins GS, Liu KJ. Interstitial po2 in ischemic penumbra and core are differentially affected following transient focal cerebral ischemia in rats. J Cereb Blood Flow Metab 2004 24 343-349. 

Anderson RE, Tan WK, Martin HS, Meyer FB. Effects of glucose and Pa02 modulation on cortical intracellular acidosis, NADH redox state, and infarction in the ischemic penumbra. Stroke 1999 30(1) 160-170. 

These observations led us to hypothesize that administration of BEO could have a neuroprotective effect against ischemic neuronal injury and that neuroprotection by BEO may stem from maintenance in the active state of endogenous survival programs only transiently activated in the ischemic penumbra. Given that BEO for systemic (intraperitoneal, i.p.) administration crosses the blood-brain barrier (BBB) in rat (Morrone et al, 2007), we considered this of special interest in view of the poor penetration into the brain of a number of neuroprotectants (Wu, 2005). 

Here we investigate the neuroprotective potential of BEO in vivo by using an experimental model of focal brain ischemia in rats. Moreover, we evaluate whether neuroprotection is associated with altered levels of excitatory neurotransmitters and with a modulation of PI3-K/Akt pathway in the ischemic cortex. Our results indicate that BEO indeed protects against ischemic injury in an in vivo model of permanent focal brain ischemia in rat and that neuroprotection is associated with reduced excitatory amino acid efflux induced by MCAo in the ischemic cortex and elevation ofp-Akt and phospho-GSK-3/3 (p-GSK-3/3) levels in the ischemic penumbra. A preliminary account of this in vivo study has been communicated to the British Pharmacologic Society (Morrone et al., 2006). 

The results of the present study show that systemic administration of BEO reduces the volume of infarct induced by MCAo in the brain of rat. Neuroprotection afforded by BEO is preceded by minimization of the MCAo-induced increase in excitatory amino acid efflux in the ischemic penumbra. Under ischemic... 

Ginsberg MD, Pulsinelli WA (1994) The ischemic penumbra, injury thresholds, and the therapeutic window for acute stroke. Ann Neurol 36 553-554... 

Especially in models of transient cerebral ischemia, apoptotic cell death has been observed after 3-7 days post insult in selected brain regions in which basal energy metabolism has been preserved (Chen et al. 1997 Du et al. 1996). In the meantime, molecular switches have been identified that gate different populations of neurons with regard to the type of cell death they eventually undergo (Nicotera 2003). However, there is little doubt that in animal stroke the vast majority of cells would die from necrosis or, alternatively, secondary energy failure even in the presence of a pro-apop-totic genetic balance. The concept of thresholds of cerebral blood flow (CBF) for various functions of brain parenchyma (see below) explains why the infarct core suffers from pan-necrosis whereas the peri-infarct border in which function is suppressed, but structure initially preserved (the so-called ischemic penumbra), may show apoptotic cell death or a combination of both. 

The concept of critical flow thresholds provides the rational basis for attempts to salvage the ischemic penumbra. In the clinical environment, the successful application of thrombolysis in stroke patients (NINDS Study Group 1995) could be shown to be related to this issue fair clinical outcome correlated positively with early recanalization (von Kummer et al. 1995) and even small improvements of local CBF in the 10% range predicted the reversibility of ischemic tissue changes (Butcher et al. 2003). 

Of greater therapeutic relevance is the zone lying peripheral to the region of dense ischemia and perfused at somewhat higher CBF levels the ischemic penumbra. In baboons subjected to MCA occlusion, CBF was measured along with the extracellular potassium concentration and sensory evoked poten-... 

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